title: NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.
abstract: Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-κB-dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.
authors.forename: Wei A
authors.initials: WA
authors.lastname: He
authors.forename: Emanuele
authors.initials: E
authors.lastname: Berardi
authors.forename: Veronica M
authors.initials: VM
authors.lastname: Cardillo
authors.forename: Swarnali
authors.initials: S
authors.lastname: Acharyya
authors.forename: Paola
authors.initials: P
authors.lastname: Aulino
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomas-Ahner
authors.forename: Jingxin
authors.initials: J
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.forename: Peter
authors.initials: P
authors.lastname: Muscarella
authors.forename: Peter
authors.initials: P
authors.lastname: Nau
authors.forename: Nilay
authors.initials: N
authors.lastname: Shah
authors.forename: Matthew E R
authors.initials: ME
authors.lastname: Butchbach
authors.forename: Katherine
authors.initials: K
authors.lastname: Ladner
authors.forename: Sergio
authors.initials: S
authors.lastname: Adamo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.forename: Dario
authors.initials: D
authors.lastname: Coletti
authors.forename: Federica
authors.initials: F
authors.lastname: Montanaro
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008819:Mice, Nude; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; C497322:Pax7 protein, mouse